Apparatus and method of research for creating and testing novel catalysts, reactions and polymers

ABSTRACT

A method and system for researching and developing and/or optimizing new catalysts and products in a combinatorial manner is disclosed. The method begins with starting components or a ligand library and provides methods of creating catalyst or product libraries, which are then tested in a reaction of interest. The system uses methods of robotic handling for moving libraries from station to station. The method and apparatus are especially useful for synthesizing, screening, and characterizing combinatorial catalyst libraries, but also offer significant advantages over conventional experimental methods as well.

[0001] This application is a divisional of U.S. patent application Ser.No. 09/620,310, filed Jul. 19, 2000, which is a divisional of U.S.patent application Ser. No. 09/227,558, filed Jan. 8, 1999, both ofwhich are incorporated herein by reference and both of which claim thebenefit of U.S. Provisional Application No. 60/080,652, filed Apr. 3,1998, the teachings of which are also incorporated herein by reference.

BACKGROUND

[0002] 1. Technical Field

[0003] The present invention relates to the field of research for newcatalysts or polymers or processes for making polymers. Moreparticularly, this invention is directed toward an apparatus and methodof performing homogeneous and supported homogeneous catalysis andrelated techniques for rapidly creating and testing catalyst librariesprepared by combinatorial techniques. This invention is also directedtoward an apparatus and method for making polymers using combinatorialtechniques.

[0004] 2. Discussion

[0005] Combinatorial chemistry has revolutionized the process of drugdiscovery. See, for example, 29 Ace. Chem. Res. 1-170 (1996); 97 Chem.Rev. 349-509 (1997); S. Borman, Chem. Eng. News 43-62 (Feb. 24, 1997);A. M. Thayer, Chem. Eng. News 57-64 (Feb. 12, 1996); N. Terret, 1 DrugDiscovery Today 402 (1996)). Because of its success in eliminating thesynthesis bottleneck in drug discovery, many researchers have come tonarrowly view combinatorial methods as tools for creating structuraldiversity. Few researchers have emphasized that, during synthesis,variations in temperature, pressure, ionic strength, and other processconditions can strongly influence the resulting properties of librarymembers. For example, reaction conditions are particularly important informulation chemistry and polymer chemistry, where one combines a set ofcomponents under different reaction conditions or concentrations todetermine their influence on product properties.

[0006] Recently, combinatorial approaches have been used for discoveryprograms unrelated to drugs. Combinatorial materials science generallyrefers to the methods for creating a collection of chemically diversecompounds or materials and to methods for rapidly testing or screeningthis library of compounds or materials for desirable performancecharacteristics and properties. For example, some researchers haverecognized that combinatorial strategies offer promise for the discoveryof inorganic compounds such as high-temperature superconductors,magnetoresistive materials, luminescent materials, and catalyticmaterials. See, for example, co-pending U.S. patent application Ser. No.08/327,513 “The Combinatorial Synthesis of Novel Materials” (publishedas WO 96/11878) and U.S. Pat. No. 5,776,359, which are both hereinincorporated by reference. Compared to traditional discovery methods,combinatorial methods sharply reduce the costs associated with preparingand screening each candidate material.

[0007] Some combinatorial research into catalysis and polymer formationhas begun. See U.S. patent application Ser. No. 08/898,715“Combinatorial Synthesis and Analysis of Organometallic Compounds andCatalysts” (published as WO 98/03251). The following articles discussone or more combinatorial techniques in conjunction with catalysis, andeach are incorporated herein by reference: Senkan, Nature, vol 394, pp.350-353 (Jul. 23, 1998); Burgess et al., Angew. Chem. Int. Ed. Eng.,1996, 35, No. 2, pp. 220-222; Maier et al., Angew. Chem. Int. Ed. Eng.,1998, 37, No. 19, pp. 2644-2647; Reetz et al., Angew. Chem. Int. Ed.Eng., 1998, 37, No. 19, pp. 2647-2650; Schlögl, Angew. Chem. Int. Ed.Eng., 1998, 37, No. 17, pp. 2333-2336; Morken et al., Science, vol. 280,pp. 267-270 (Apr. 10, 1998); and Gilbertson et al., Tetrahedron Letters,vol. 37, no. 36, pp. 6475-6478 (1996).

[0008] What is needed is a combinatorial method and apparatus for theresearch, discovery and development of catalysts and polymers. Thisinvention advances the field by providing an entire system, beginningwith a ligand library or a set of reactants and ending with screens forperformance, with a variety of reaction and screening options.

SUMMARY OF THE INVENTION

[0009] This invention provides methods and apparatus for performing thecombinatorial synthesis of libraries and screening of thosecombinatorial libraries. This invention gives those of skill in the arta variety of synthesis and screening techniques so that a completecombinatorial discovery or optimization research and development programcan be successfully implemented for many different reactions, includingall types of polymerizations or small molecule catalysis. The broadestconcept of the methodology is that a library is created that is screenedfor a property or compound of interest. The libraries that are createddepend on the reaction of interest, but are typically either catalystlibraries or product libraries. This invention provides a number ofembodiments for performing such synthesis and screening and theembodiments may be combined together.

[0010] One embodiment of the present invention is a method and apparatusfor researching for novel catalysts by starting with a ligand librarythat includes a plurality of member ligands. In the ligand library (alsoreferred to as a parent ligand library) each ligand member may have acommon scaffold, but will vary in structural diversity. The ligandlibrary may also include ligand members that have different scaffolds.The important point is that the ligand library includes ligand membersthat are different from each other by either scaffold or structuraldiversity or both. Optionally, one or more daughter libraries arecreated from the parent ligand library by taking one or more aliquotsfrom one or more member ligands in said ligand library. For example,each daughter library may be considered to be a replica of the ligandlibrary, but each daughter ligand member would be smaller than theparent ligand member in terms of either volume or moles or mass. Atleast one metal precursor is added to at least a portion of the membersof the ligand libraries or daughter libraries to create one or morecatalyst libraries. The catalyst library is subjected to a reaction ofinterest. The reaction of interest may be a reaction that creates aproduct library. For example, if the reaction of interest is apolymerization reaction, a polymer library will be the result.Alternatively, the reaction of interest may be a screen for activity.The reaction of interest can have process conditions that arecombinatorialized, such as varying amounts of reactants or differentconditions (such as time, temperature, pressure, atmosphere, etc.). Themethod optionally provides different screening stages, such as a primaryscreen to eliminate some members from a library from going on to asecondary screen.

[0011] In another embodiment, mixtures of starting components (such asligands, metal precursors, initiators, monomers, solvents, etc.) arecombined in different ratios. A reaction of interest is performed undervarying conditions to create a product array. This embodiment focuses oncombinatorializing the conditions of the reaction of interest. Processconditions that may be combinatorialized include amounts (volume, molesor mass) and ratios of starting components, time for reaction, reactiontemperature, reaction pressure, rate of starting component addition tothe reaction, residence time (or product removal rate), reactionatmosphere, reaction stir rate and other conditions that those of skillin the art will recognize. The library that is created in thisembodiment is a product library that is then screened for a property orcompound of interest. Optionally, prior to screening, the productlibrary is daughtered into one or more daughter product libraries.

[0012] In addition, the two above embodiments can be combined together.For example, this invention may be practiced in order to discover apolymer of interest by free radical polymerization (e.g., a polymerhaving predetermined properties, such as molecular weight or particlesize). The library of polymers (e.g., a product library) may be createdby having diversity in the starting components used or by havingdiversity the reactions conditions (e.g., time, temperature, mixingspeed, etc.). The polymer library is then tested to determine if apolymer of interest has been created using one of many different rapidpolymer characterization techniques. Thus, in this example, the screenmay be the reaction, the polymer characterization or both.

[0013] The embodiments of this methodology are combined into a flexiblesystem that includes a number of different stations including one ormore stations for combining starting materials, daughtering thelibraries, performing the reactions of interest and screening theresults of the process. The system includes a control system thatcontrols, monitors and directs the activities of the system so that auser may design an entire series of experiments by inputting librarydesign, screening or data manipulation criteria.

[0014] Those of skill in the art will appreciate the variety of methodsfor creating diversity in the libraries of this invention. The screensthat are provided to determine if the diversity has produced a productof interest complete the research and development methodology.

[0015] A further understanding of the nature and advantages of thepresent invention may be realized by reference to the remaining portionsof the specification and the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIGS. 1A and 1B show a generic ligand having a scaffold andstructural diversity and a ligand library, respectively.

[0017]FIG. 2 is a flowchart depicting an overall method for oneembodiment of the invention.

[0018]FIG. 3 is a cut-away perspective illustration of a glass linedparallel batch reactor useful in this invention.

[0019]FIG. 4 is a block diagram illustration of rapid molecular weightlight scattering characterization equipment that was used in theExample.

[0020]FIG. 5 is block diagram illustration of an overall method andapparatus of this invention.

[0021]FIG. 6 includes FIGS. 6A-6C and shows details of a library storagerack and plate system useful in this invention.

[0022]FIG. 7 is a partial view of one embodiment of the apparatus ofthis invention.

DETAILED DESCRIPTION

[0023] There are two principal features to this invention: (1) creatinga library having diversity and (2) screening that library for a propertyor compound of interest. A library in this invention has either chemicaldiversity or process diversity. Chemical diversity refers to a libraryhaving members that vary in atoms or molecules. Process diversity refersto a library having members that may have begun with the same atoms ormolecules, but with members that have been subjected to differentprocessing conditions and are different as a result of those differentprocessing conditions. Different processing conditions include varyingamounts (volume, moles or mass) and ratios of starting components, timefor reaction, reaction temperature, reaction pressure, rate of startingcomponent addition to the reaction, residence time (or product removalrate), reaction atmosphere, mixing or stir rate and other conditionsthat those of skill in the art will recognize. It is through thecreation of libraries having diversity and the screening of thatdiversity for a property or compound of interest that a completecombinatorial research and development program may be undertaken forhomogeneous catalysis or supported homogeneous catalysis or initiatedpolymerization reactions.

[0024] In one embodiment, this invention is directed to rapid creationand testing of novel catalysts, but offers significant advantages overconventional experimental methods and systems. For example, the presentinvention allows for automated parallel catalyst creation and screeningof multiple synthetic routes to targeted catalysts, thereby saving timeand conserving valuable reactants in determining appropriate catalystsfor catalyzing a pre-selected reaction. This invention also provides avariety of screening options, allowing for flexibility in choosing theappropriate reaction flow and conditions for a reaction of interest.

[0025] For example, if a coordination polymerization reaction is thereaction of interest, this invention provides the method and apparatusfor the synthesis of organometallic complex libraries by a variety ofroutes that may be catalysts. Optional activation of thoseorganometallic complexes into catalysts is included. After the catalystlibraries are prepared the invention provides for screening of thecatalyst libraries. Screening may be in, for example, a parallelpolymerization reactor that provides detailed information aboutcatalytic activity under a variety of reaction options and conditions,including monomer and comonomer choice, solvent, pressure, temperature,stirring rate, volume, stoichiometric relationships and order ofaddition of chemicals. Thus, one may chose to “combinatorialize” thepolymerization reaction conditions for a single catalyst library.Optional steps in this example coordination polymerization combinatorialprocess include a primary screen prior to screening in the parallelpolymerization reactor. A primary screen may, for example, comprise anoptical screen under polymerization conditions that simply determineswhich members of the catalyst library have any activity. Anotheroptional step is to further characterize the resultant polymers formedin the parallel polymerization reactor. Such further screening mayemploy a rapid liquid chromatography and/or light scattering system,such as those described in U.S. Provisional Application No. 60/080,652,filed Apr. 3, 1998, which is incorporated herein by reference. Such afurther screen may also determine the physical or melt flow propertiesof the resultant polymers, such as with a sensor-array based system suchas is disclosed in U.S. patent application Ser. No. 09/210,485, filedDec. 11, 1998, which is incorporated herein by reference.

[0026] Thus, the flexibility of this invention can be seen by those ofskill in the art from the variety of options that a complete systemoffers, including choosing starting components (e.g., ligands and metalprecursors), choosing reaction or coordination routes for the creationof catalyst libraries, choosing screening reactors and reactionconditions and choosing characterization methods and apparatus.

[0027] In other embodiments, this invention discloses methods forrapidly forming polymer product libraries from at least an initiator anda monomer. A variety of monomers and initiators can be chosen, alongwith other polymerization additives, such as solvents, co-initiators,modifiers, surfactants, etc. Those of skill in the art know of suchadditives. A parallel reactor is used for the reaction and the parallelreactor may have internal sensing capabilities providing real timeproperty characterization for certain properties, such as viscosity. Theparallel reactor may also provide the ability to vary reactionconditions from one reactor vessel to another so that the polymerizationconditions may be combinatorialized. The polymer libraries may then befurther characterized using rapid polymer characterization techniques.Thus again, the flexibility of this invention can be seen by those ofskill in the art from the variety of options that a complete systemoffers, including choosing initiators, choosing monomers, choosingmethods and conditions of reaction for the creation of polymerlibraries, and choosing characterization methods and apparatus. In thismanner a complete combinatorial polymer discovery or optimizationresearch and development program may be undertaken.

[0028] As discussed herein there are three fundamental types oflibraries: a ligand library, a catalyst library and a product library.The three types of libraries may or may not be used in the sameembodiment of the invention.

[0029] A ligand library is a library comprised of member ligands.Typically, a ligand library has chemical diversity. As used herein,chemical diversity within the ligand library is divided up between avariety of scaffolds and structural diversity elements. Referring toFIG. 1A, member ligands 100 of the ligand library 10 include a scaffold120, which those of skill in the art may also refer to as a backbone.There is at least one scaffold in a parent ligand library. However,there may be 2, 3, 4, 5 or more different scaffolds in a ligand library.The number of scaffolds will depend on how the library was formed or howthe library was stored. If, for example, ligands from different ligandsynthesis procedures were stored together as a single library, theligand library will be the result of this combination and any number ofdesired ligand scaffolds may be included in the ligand library.

[0030] Also, there is a plurality of different ligands in a ligandlibrary. Thus, if there is one scaffold there are typically at leastfour or five different structural diversity elements off of thescaffold. Referring to FIG. 1A, the structural diversity elements 140are shown as R groups. The member ligands in the ligand library aretypically stored or provided in a spatially addressable format, meaningthat each ligand is separated from the others. However, pooled ligandlibraries may also be used if catalytic activity can be separated todetermine which catalyst caused certain observed activity, such as witha tagging or coding technique. See, e.g., U.S. application Ser. No.09/033,207, filed Mar. 2, 1998, which is incorporated herein byreference.

[0031] Thus, the ligand library 10, shown in FIG. 1B, may include ligandmembers having one scaffold in different columns, B1, B2, etc. along theB direction and may have differing structural diversity in differentrows A1, A2, etc. along the A direction. In one embodiment of thepresent invention, the ligand library 10 is made up of a plurality ofmember ligands 100 that have a common scaffold with each member ligandbeing structurally diverse, as represented by the different positioningof R-groups 140 on scaffold 120 in FIG. 1A. In that embodiment, usingthe representation in FIG. 1B, only one column, e.g., B11, would bepresent in the patent library. In another embodiment, the ligand libraryis made up of member ligands having different scaffolds, wherein theligand members in a scaffold group are structurally diverse, meaning B1,B2, B3, etc. are present in the ligand library. Of course, the ligandlibrary may also include standards, blanks, controls or other membersthat are present for other reasons. Also, the ligand library may havetwo or more members that are identical as a redundancy option or whenreaction conditions are to be combinatorialized. The member ligands ofthe ligand library are preferably solids so that the ligand library maybe easily stored, however, the ligand libraries may also be stored insolution. When a solid phase stored ligand library is going to be usedto create catalyst libraries, the solid member ligands may be dissolvedin a suitable solvent.

[0032] There are many possible example ligand libraries. Several ligandlibraries have been described in detail in copending, commonly assignedU.S. patent applications, including U.S. application Ser. No.09/037,162, filed Mar. 9, 1998; U.S. application Ser. No. 09/119,318,filed Jul. 20, 1998; U.S. application Ser. No. 09/062,128, filed Apr.17, 1998; U.S. application Ser. No. 09/168,772, filed Oct. 8, 1998; andU.S. application Ser. No. 09/146,206, filed Sep. 2, 1998. Each of theseapplications is incorporated herein by reference for all purposes.

[0033] The ligand library may be created by combinatorial chemistrymethods similar to those that are described in co-pending U.S. patentapplication Ser. No. 08/327,513 “The Combinatorial Synthesis of NovelMaterials” (published as WO 96/11878) and co-pending U.S. patentapplication Ser. No. 08/898,715 “Combinatorial Synthesis and Analysis ofOrganometallic Compounds and Catalysts” (published as WO 98/03251),which are both herein incorporated by reference. Others have disclosedmethods for preparing enormous libraries of ligands. See for exampleU.S. Pat. Nos. 5,143,854, 5,424,186 and 5,288,514 and WO 92/10092, eachof which are incorporated herein by reference. The method of synthesisof a parent ligand library is not critical to this invention. Indeed insome embodiments, ligand libraries may be purchased. One or more ligandlibraries may be stored and retrieved from a storage rack for transferto either the daughtering station or a diluting station or a dissolutionstation, as discussed below. Such retrieval and transfer to anotherstation may be automated using known automation techniques, such asthose disclosed in WO 98/40159, incorporated herein by reference.Robotic apparatus is commercially available, for example from Cavro,Tecan, Robbins, Labman, Bohdan or Packard, which are companies thatthose of skill in the art will recognize.

[0034] One option for the creation of the ligand library is shown inFIG. 2. Ligand precursors 20 are formed into a parent ligand library 10.The parent ligand library 10 is initially tested at a preliminarytesting station 30 to determine if the desired ligand members have beensynthesized successfully. There may be bulk manufacturing 40 and bulkstorage 50 of the parent ligand library, so that each member is made ingreater quantities and optionally stored for future multiple testing ofthe same parent library ligand members in different reactions ofinterest or under different reactions conditions or for combining withdifferent metal precursors or activators or modifiers. In embodimentsusing bulk manufacture and storage, the ligand members in the ligandlibrary may be in solid form. The solid ligand members are typicallydissolved or diluted in a suitable solvent in a dissolution or dilutionstep 60 to provide the parent ligand library 10 with member ligands 100in a liquid form at point 70 in FIG. 2. Dilution or dissolution may bemanual or automatic, such as with known liquid handling robots. Otherprocessing conditions of dissolution or dilution may also be controlled,such as using a glove box for an inert atmosphere during dilution ordissolution. The temperature of the operation may also be controlled byproviding a heating/cooling block, such as that disclosed in commonlyassigned U.S. application Ser. No. ______, filed Nov. 19, 1998 (havingattorney docket no. 65304-014) and incorporated herein by reference. Inother embodiments, the ligand library is provided in a liquid form, forexample with each ligand stored in a separate vial. In thoseembodiments, the parent ligand members may be stored in a vial having aseptum that can be penetrated by a needle that may be on a robotic armof known liquid handling robots. Optionally, as shown in FIG. 2 also,the bulk steps or storage can be eliminated so that the parent ligandlibrary 10 goes directly from synthesis to point 70 in FIG. 2.

[0035] The next type of library is a catalyst library, which is acollection of potentially catalytic compounds or compositions. Themembers are potentially catalytic depending on the reaction of interest,i.e., a member may be active in one reaction of interest, but inactivein a different reaction of interest. The catalyst library is formed fromthe combination of ligands and metals. The catalyst library may beformed from the combination of a ligand library and a metal precursor.In other embodiments, the catalyst library is formed from thecombination of a metal precursor library and a ligand. For example,combining comprises adding at least one ligand member from the ligandlibrary to at least one metal precursor. More typically, at least fourligand members, at least 10 ligand members, at least 25 ligand members,at least 50 ligand members or at least 96 ligand members are providedthat are each combined with at least one metal precursor. Also forexample, combining comprises adding at least one metal precursor memberfrom a metal precursor library to at least one ligand.

[0036] There are a number of methods for combining metal precursors withthe ligand members of the library. In some embodiments, the same metalprecursor is added to the ligand members (whether the members havedifferent scaffolds or not) or different metal precursors are added todifferent ligand library members. In other embodiments, a differentmetal precursor is combined with each member ligand having a differentscaffold such that the number of different metal precursors is equal tothe number of different scaffolds. In still other embodiment, differentmetal precursors are added to ligand members having different structuraldiversity elements. Combining different metal precursors with differentligand library members provides the opportunity to try different routesfor the formation of the same or similar metal-ligand complexes orcompositions. In other embodiments, the ligand members will be mixedwith a suitable metal precursor prior to or simultaneous with allowingthe mixture to be contacted to the reactants in the next library ortesting phase of the invention. When the ligand member is mixed with themetal precursor, a metal-ligand complex may be formed, which may be acatalyst.

[0037] Metal precursors may take the form of a metal atom, ion, compoundor other metal precursor compound. In some embodiments, the memberligands may be combined with a metal precursor and the product of suchcombination is not determined, if a product forms at all. For example,the ligand member may be added to a reaction vessel at the same time asthe metal or metal precursor compound along with additional reactants inthe reaction of interest. As such, the result of the combination is notdetermined. The metal precursors may be characterized by the generalformula M(L)n where M is a metal selected from the group consisting ofGroups 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 of the Periodic Tableof Elements. Specific metals include Sc, Y, La, Ti, Zr, Hf, C, Nb, Ta,Cr, Mo, W, Mn, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn,Cd, Al, In, Tl and Sn. L is a metal-ligand chosen from the groupconsisting of halide, alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy,hydroxy, boryl, silyl, hydrido, thio, seleno, phosphino, amino, andcombinations thereof. When L is charged, L is selected from the groupconsisting of hydrogen, halogens, alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, heterocycloalkyl, substitutedheterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, aryloxy, acetoxy, silyl, boryl, phosphino, amino,thio, seleno, and combinations thereof. When L is neutral, L is selectedfrom the group consisting of carbon monoxide, isocyanide,dibenzylideneacetone, nitrous oxide, PA₃, NA₃, OA₂, SA₂, SeA₂, andcombinations thereof, wherein each A is independently selected from agroup consisting of alkyl, substituted alkyl, heteroalkyl, cycloalkyl,substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,aryloxy, silyl, and amino. The ligand to metal precursor ratio isdetermined by the research program of interest, and for example may bein the range of about 0.01:1 to about 100:1, or more specifically in therange of about 0.5:1 to about 20:1.

[0038] Depending on the ligand library, it may be necessary toadditionally combine a ligand modifier 208 with member ligands 202 ofthe ligand libraries, as shown in FIG. 2. If there are different ligandmodifiers 208, they may be in a ligand modifier library 210 and may beadded to the ligand libraries 200 at the same time as the metalprecursor(s) or prior to serve to produce modified ligand librariesbefore combining the ligand members with the metal precursors to achievethe desired target catalysts. The purpose of a ligand modifier is toallow or assist the ligand to coordinate to or bond with a metal atom,ion or precursor. The ligand modifier is generally a deprotonation agentthat modifies the ligand at the position(s) where the ligand coordinatesto or bonds with the metal atom, ion or precursor. Ligand modifiersinclude deprotonating agents such as alkyl lithium compounds (such asmethyl lithium or butyl lithium) and lithium diisopropyl amine. Those ofskill in the art know many ligand modifiers that are useful in thisinvention.

[0039] Another option in forming the catalyst libraries is to provide anactivator. When there is more than one activator, the activators may beprovided in an activator library 214. The activator or activatingtechnique includes the use alumoxanes, strong Lewis acids, compatiblenoninterfering activators and combinations of the foregoing. Theforegoing activators have been taught for use with metal complexes inthe following references, which are hereby incorporated by reference intheir entirety: U.S. Pat. Nos. 5,599,761, 5,616,664, 5,453,410,5,153,157, 5,064,802 and EP-A-277,004.

[0040] There are a number of methods for combining the ligand modifiersor activators with the ligand libraries and metal precursors. In someembodiments, the same ligand modifiers or activators are added to themembers of the daughter library (whether the members have differentscaffolds or not) with the metal precursor. Alternatively, differentligand modifiers or activators are added to different ligand libraries.In other embodiments, a different ligand modifier or activator iscombined with each member ligand in the ligand libraries having adifferent scaffold such that the number of different ligand modifiers oractivators is equal to the number of different scaffolds for each memberligand. In still other embodiment, different ligand modifiers oractivators are added to daughter library members having differentstructural diversity elements. Combining different ligand modifiers oractivators with different ligand members provides the opportunity to trydifferent routes to the formation of the same or similar catalystlibraries.

[0041] Thus, combining ligands, metal precursors, optionally ligandmodifiers and optionally activators (or activating techniques) providesthose of skill in the art powerful options for following differentchemical routes for the formation of the same or a similar catalyst. Theuse of different chemical routes to the same or similar catalyst incombinatorial materials science may minimize the chances of missing anactive catalyst for a reaction of interest. One specific example of theuse of different chemical routes for formation of the same or similarpolymerization catalysts is in the field of cationic metallocenecatalysts stabilized by compatible anions (see e.g., U.S. Pat. No.5,599,761 or 5,817,849, both of which are incorporated herein byreference). One route to the formation of such catalysts is through theuse of ion exchange activators. A second route is through the use ofLewis Acids. A third route is through the use of oxidative activators.The result of each route is an active catalyst having substantially thesame structure, which produces substantially the same result undersimilar polymerization conditions.

[0042] A third type of library is a product library. A product libraryis the result of running a reaction of interest. Starting components areadded to a reactor and a reaction of interest is run to form the productmembers of the product library. A product library obtains its diversityeither by chemical diversity in the starting components or by processdiversity or both and both types of diversity are discussed above. Thus,a product library may be the result of testing a catalyst library in areaction of interest run under the same or different process conditions.A product library also may be the result of beginning with the samestarting components and testing those components under differentprocessing conditions. Specifically not within the scope of thisinvention is the formation of product libraries having members that arebiological polymers, such as polymers made from alpha amino acids andnucleotides. Examples of polymers that may be members of a productlibrary include homopolymers, copolymers or higher order polymers likepolyethylenes, polyurethanes, polyesters, polycarbonates, polyacetates,polystyrenes, polyamides, and the like.

[0043] Starting components for forming a product library are thosecomponents needed for performing the reaction of interest. Reactions ofinterest include those selected from the group consisting ofcarbonylation, hydroformylation, hydroxycarbonylation,hydrocarbonylation, hydroesterification, hydrogenation, transferhydrogenation, hydrosilylation, hydroboration, hydroamination,epoxidation, aziridination, reductive amination, aryl amination,polymerization, oligomerization, C—H activation, insertion, C—Hactivation-insertion, C—H activation-substitution, C-halogen activation,C-halogen activation-insertion, C-halogen activation-substitution,cyclopropanation, alkene metathesis, and alkyne metatesis. Those ofskill in the art know what starting components are needed for each ofthese types of reactions.

[0044] Starting components include catalysts, ligands, metal precursors,ligand modifiers and activators as discussed above. Starting componentsalso include monomers, solvents, initiators, scavengers andsurfactants/emulsifiers. Starting components that are monomers that haveat least one addition-polymerizable unsaturated bond, including olefins,diolefins, allyl esters, vinyl ethers, vinyl esters, vinyl heterocycliccompounds, stryrenes, halogenated olefins, crotonic acids, vinylketones, itaconic acids and esters, unsaturated nitriles, acrylic ormethacrylic acids and esters, acrylamides and methacrylamides andcombinations thereof (see, e.g., U.S. Pat. No. 5,244,763, incorporatedherein by reference). Example of solvents include polar and non-polarsolvents and ionic solvents and may include alkanes, heterocycliccompounds, chlorinated compounds, water, and combinations thereof.Surfactants may be cationic, anionic, zwitterionic or non-ionic,including combinations thereof. Initiators may initiate a cationic,anionic or free radical reaction, and include inorganic salts, peroxycomounds and the like (see, e.g., U.S. Pat. No. 5,594,047, which isincorporated herein by reference). For example, for coordinationpolymerization, the starting materials include monomers, solvent,catalyst libraries (either activated or not) and scavengers. Also forexample, for a free radical polymerization, the starting componentscomprise at least an initiator and a monomer. Other starting componentsinclude co-initiator, co-monomers, solvents, surfactants, emulsifiers orother additives. In forming a product library, the starting materialsmay be varied with respect to each other in terms of volume, moles ormass. In varying the starting materials, the types of ratios that can bevaried include monomer to initiator; monomer A to monomer B; solvent tomonomer; surfactant to initiator; catalyst to activator; andcombinations thereof.

[0045] The product library has different members possibly as the resultof combinatorializing the process variables in the reaction of interest.Process variables that may be combinatorialized include the amounts(volume, moles or mass) and ratios of starting components, time forreaction, reaction temperature, reaction pressure, rate and/or method ofstarting component addition to the reaction (or reactor), residence time(i.e., rate and/or method of product removal from the reaction orreactor), reaction stir rate and/or method, reaction kill rate and/ormethod, reaction atmosphere and other conditions that those of skill inthe art will recognize. The product libraries are created using one ofthe parallel reactors discussed below, including the parallel solutionreactor, the continuous feed reactor, the multi-temperature reactorblock, the parallel batch reactor or another parallel reactor that maybe known such as in U.S. Pat. No. 4,099,923, which is incorporatedherein by reference.

[0046] Therefore, those of skill in the art will appreciate the vastnumber of different possible combinations of ligands, metal precursors,modifiers, activators or other starting components that may be combinedtogether to form the catalyst libraries. In addition, this combinationmethodology may be combined with combinatorializing of various reactionconditions, including different starting component ratios, differenttemperatures, solvents, pressures, mixing rates, times, order ofaddition of chemicals or atmospheres to form vastly different productlibraries. For example a multiple temperature reactor block, such asdiscussed below, may be used to provide different temperature andpressure options. Also optionally, the combining of ligands 202, metalprecursors 204, modifiers 208 or activators 212 may take place in thereactor being used for the reaction of interest. Combining may be donejust before the reaction of interest or may be done well before thereaction of interest.

[0047] In the methodology of this invention, a library is screened for aproperty or compound of interest. Depending on the embodiment beingpracticed, the screen may look for the existence of a particularcompound or for a particular property. For example, when free radicalpolymerization is the reaction of interest, the screen may look formolecular weight or particle size. Also for example, when aryl aminationis the reaction of interest, the screen may look for the amine that thereaction is intended to form. The screening may take place as thereaction of interest is being performed. As used herein, “screening”refers to testing a library for one or more properties or compounds ormaterials. Also as used herein, “reaction” refers to a chemicaltransformation (e.g., amination or polymerization). A screen may becombined with a reaction of interest, but the two may also be separate.For example, polymerization reactions performed in stirred tank parallelpolymerization reactors are both a reaction and a screen because apolymerization reaction is performed and catalyst activity can bemonitored by gas monomer uptake or by temperature increase or by anin-reactor sensor or by lag in a stirrer, providing testing of theproperties of the catalyst or polymer. Also for example, apolymerization reaction performed in a batch reactor block would beconsidered to be only a reaction of interest if there is no monitoringas the reaction is proceeding. Also for example, nuclear magneticresonance (NMR) or gas chromatography (GC) and mass spectrometry (MS)are only screens because they determine the results of the reaction ofinterest, which was performed in a separate reactor.

[0048] Each of the three types of libraries may be stored in a liquid orsolid state and retrieved from storage for combining, daughtering,running in the reaction of interest or screening or combinationsthereof. Libraries are preferably stored in a storage rack that holdsthe libraries separately from each other. Libraries may be retrievedfrom storage either manually or automatically, using known automatedrobots. Specific robots useful for retrieving such stored librariesinclude systems such as those marketed by Aurora Biosciences or otherknown robotic vendors. If the libraries are stored in the solid phase,the members typically require dissolution, which is performed at adissolution station, which may be the combining station (discussedbelow) or may be in addition to the combining station. A dilutionstation is a location where the library members are dissolved in asuitable solvent for use in either the reaction of interest or in ascreen.

[0049] Also, each of these types of libraries may be daughtered into oneor more daughter ligand libraries, daughter catalyst libraries ordaughter product libraries, respectively. A daughter library is createdfrom the parent library at a daughtering station by taking one or morealiquots from one or more members in the parent library, wherein analiquot is a definite fraction of a whole. This process is referred toas “daughtering.” Literally, a liquid pipette, operated either manuallyor automatically (e.g., robotically), draws a bit of a member from theparent library and dispenses that aliquot into another container to givea daughter library member. A limited number of members of the parentlibrary may be daughtered or all the members may be daughtered at leastonce to create one daughter library. Thus, a daughter library may besmaller than the parent library in terms of either mass, volume or molesand/or in terms of the number of members. In other embodiments, themembers of the parent library are maintained in a solid form. During thedaughtering process known solid handling equipment and methods are usedto take the aliquot from the parent library to created the daughterlibrary, which will have members that are also solids. Thereafter, itmay be necessary to dissolve the members of the daughter libraries in asolvent. Daughtering is performed in order to provide multiple librariesfor multiple reactions of interest or multiple screens without having torecreate the parent library.

[0050] Optionally a filtering station is provided, which is preferably aparallel filtering station. The filtering station is useful to filteroff solid phase agents or products from liquid products or precursors.For example, in some embodiments the metal precursors will be providedin solid-phase form, such as the solid phase metal delivery agentsdisclosed in commonly assigned U.S. patent application Ser. No.09/025,841, filed Feb. 19, 1998, incorporated herein by reference. Thesolid-phase metal precursors allow for synthesis of the catalystlibraries in the solution phase and then filtering off the solid-phasemetal precursor. A filtering station provides for ease in the synthesisof the catalyst libraries or the ligand libraries. The ligands, metalprecursors, ligand modifiers or activators may be provided in the solidphase (e.g., on a bead or other support) allowing for ease in ligand orcatalyst preparation. Solid phase combinatorial synthesis of ligands iswell known. See, e.g., Ellman et al., “Solid-Phase Synthesis:Applications to Combinatorial Libraries”, Annu. Rep. Med. Chem., 1996,31, pp. 309-318; Rees et al. “Solid-Phase Organic Reactions: A review ofthe Recent Literature”, Tetrahedron, Vo. 52, No. 13, pp. 4527-4554,1996; and Kaldor and Siegel, “Combinatorial chemistry usingpolymer-supported reagents”, Currents Opinion in Chemical Biology, 1997,1:101-106; each of which are incorporated herein by reference. Solidphase agents or reagents in association with combining generally allowsfor the use of excess agents or reagents, ease of purification orwork-up and automating the process.

[0051] Reactions of interest may be performed in a parallel reactorchamber or a parallel reactor block. Looking first at reactors that alsocontain screening capabilities, parallel reactors that are useful withthis invention include a parallel solution reactor with internal sensingas disclosed in U.S. patent application Ser. No. 09/177,170, filed Oct.22, 1998 and its improved version, U.S. patent application Ser. No.09/211,982, filed Dec. 14, 1998 (having attorney docket no. 65304-059).This reactor includes internal sensing and thus is also a screen. Thisparallel reactor allows for the variation of several differentprocessing conditions, and therefore allows one to combinatorializereaction conditions or process variables. For example, a mechanicalresonator (e.g., a tuning fork) may be the sensor that detects product,compound, reactant or reaction properties. In another embodiment theparallel reactor may be a closed chamber with a tuning fork in thereactor, as disclosed in U.S. patent application Ser. No. 08/946,921,filed Oct. 8, 1997, which is incorporated herein by reference (publishedas WO 98/15501, which is also incorporated herein by reference).

[0052] Another parallel reactor that also includes screening capabilityis an optical screen, using infrared (IR) thermography or FourierTransform Infrared (FTIR) spectroscopy or visible light or other opticalviewing as disclosed in copending U.S. patent application Ser. No.08/946,135, filed Oct. 7, 1997, (published as WO 98/15815) or incopending U.S. patent application Ser. No. 08/947,085, and filed Oct. 8,1997, (published as WO 98/15805). These applications are incorporatedherein by reference. Using an optical technique typically entailsinserting the starting materials (e.g., catalyst library member withreactants or initiator with monomer) in an array format into a chamber(for example, a vacuum chamber or a chamber pressurized with reactantmonomer or a chamber pressurized with an inert gas). The reaction ofinterest is performed in parallel in the chamber using a plate havingmultiple wells for the catalyst members or starting materials for theproduct members (such as a microtiter plate, for example). The chamberhas a window that is invisible to the optical camera (e.g., calciumfluoride or saphire crystal for an IR camera). As the reaction ofinterest is carried out, the optical camera monitors the reaction withactive catalyst or polymer members meeting a specified property orcharacteristic. Alternatively, for example, a dye may be inserted intothe reactor vessel array and the camera may monitor a color change. Alsofor example, an IR camera may monitor heat of reaction for exothermicreactions.

[0053] Another reactor/screen is related to thin layer chromatography(“TLC”), as described more fully in U.S. patent application Ser. No.09/149,586, filed Sep. 8, 1998, entitled “Sampling and Analysis ofReactions by Trapping Reaction Components on a Sorbent,” incorporatedherein by reference. In TLC screening, a reactant is added to themembers of the catalyst library, thereby causing a reaction. A thinlayer of sorbent is disposed on the plate, so as to cover the wellscontaining the catalysts. Vapor product resulting from the reactionsthen contacts the sorbent in discrete areas (heating may be necessary).In some cases, visual inspection is sufficient to determine activecatalysts. But, a use of a commercially available florescent indicatorreagent may be sprayed onto the sorbent, with the sorbent being exposedto ultra-violent light. A charge-coupled device camera or spectrumanalyzer then captures intensity readings of the products on the sorbentto indicate which particular catalysts are desirable for thosereactions.

[0054] Turning to reactors that do not include screening, other parallelreactors useful in this invention include a multi-temperature parallelreactor as disclosed in U.S. patent application Ser. No. ______, filedNov. 19, 1998 (having attorney docket no. 65304-014) and a continuousfeed parallel reactor as disclosed in U.S. patent application Ser. No.09/205,071, filed Dec. 4, 1998 (having attorney docket no. 98-32). Theseapplications are incorporated herein by reference. These reactorstypically include the ability to combinatorialize certain processvariables, such as temperature, time, feed rate, mixing rate, etc. Ofcourse, the reactants, catalysts, initiators, etc. can also be modifiedor combined in different amounts (different moles, volume or mass).Another parallel reactor useful in this invention is a parallel batchreactor. Such a reactor is shown in FIG. 3. FIG. 3 shows a batch reactor300 having a reactor block 302 with a plurality of wells 304 forreceiving a plurality of reactor vessels 306. To seal the reactorvessels 304, a sheet 308 is placed over the top lip of the plurality ofreactor vessels 306 and a top plate 310 is fastened to the reactor block302. Fastening may be by bolts, clips, clamps, wing nuts or otherfastening methods known to those of skill in the art. Bolts 312 areshown in FIG. 3 as the fastening method and the bolts 312 are screwedinto threads drilled into the reactor block 302. Materials useful as thereactor block and top plate include aluminum, steel or other metals,with aluminum being preferred for its thermal transfer properties. Thereactor vessels 306 may be plastic or glass, with glass being preferred.The sheet 308 is typically made from a material that is chemicallyresistant to the reaction of interest taking place in the reactorvessels as well as being elastic for its sealing properties. The sheet308 may be selected from the group consisting of Teflon®), siliconerubber, Vitron®, Kalrez® or equivalents. Parallel batch reactors of thistype are useful for the reactions of interest discussed above, and maybe heated. Mixing/stirring balls may be added to the parallel batchreactor, which may then be placed on a rocking or rotating plate fixedwith a heating element for mixing and heating the reaction contents.Alternatively, magnetic stirrers may be placed in the vessels and thereactor block may be placed on a heater/stirrer plate to affordagitation and heating. Known liquid-handling robots may be used todispense reactants, etc. into the batch parallel reactors, but manualdispensing may also be used.

[0055] Screens may be performed after the reaction of interest has takenplace. Such screens are typically for a property or a chemical ofinterest. In addition to the screens discussed above, screens includesolid-phase staining, as disclosed in U.S. patent application Ser. No.09/067,448, filed Apr. 27, 1998, which is incorporated herein byreference. Solid-phase staining uses stains to determine if a desiredchemical transformation has taken place by either observing a colorchange or the lack of a color change in a dye that is inserted into thereaction of interest. Parallel TLC may also be used as a screen in thisinvention, as disclosed in U.S. patent application Ser. No. 09/062,128,filed Apr. 17, 1998, which is incorporated herein by reference. Adepolarized light scattering array may screen the reactions of interestin an apparatus and method disclosed in U.S. patent application Ser. No.09/174,986, filed Oct. 19, 1998, which is incorporated herein byreference. Also, rapid thermal analysis, using a sensor array may beused, as disclosed in U.S. patent application Ser. No. 09/210,485, filedDec. 11, 1998 (having attorney docket no 65304-039), which isincorporated herein by reference. Those of skill in the art willrecognize that NMR, GC/mass spectrometry, and LC/mass spectrometry,which are commercially available, may also be used for screening productlibraries. Finally, rapid polymer characterization techniques may beused, as discussed in U.S. Provisional Patent Application No.60/080,652, which is incorporated herein by reference.

[0056] One method and system disclosed herein utilizes a parent ligandlibrary having a plurality of member ligands as an initial startingpoint in generating one or more catalyst libraries. In some embodiments,an important feature of the parent ligand library is chemical diversitywithin the library. This invention will allow such chemically diverseligand species to be tested parallel. In other embodiments, a single orfew ligands will be used repeatedly in a variety of reactions under avariety of conditions for optimization of a reaction with a particularcatalyst. With the parent ligand library provided, the next step isoptional and entails forming one or more daughter libraries 200 from theparent library 10, as shown in FIG. 2. Literally, a liquid pipette,operated either manually or automatically (e.g., robotically), draws abit of liquid member ligand 100 from the ligand library 10 at point 70and dispenses that aliquot into another container to give a daughterlibrary member ligand 202. Point 70 in FIG. 2 can be considered adaughtering station. In accord with this invention, a portion of theligand library 10 may be daughtered at least once to create one daughterlibrary 200. Thus, creation of the one or more daughter libraries 200may be only for a portion of the ligand library 10 member ligands 100.More typically, however, each member of the ligand library is daughteredto one or more daughter libraries 200, as is shown in FIG. 2. After thedaughtering step, the daughter libraries 200 may be dried or stored in amanner similar to the parent ligand libraries. In other embodiments, themember ligands 100 of the ligand library 10 are maintained in a solidform. During the daughtering process known solid handling equipment andmethods are used to take the aliquot from the ligand library to createdthe daughter library, which will have members that are also solids.Thereafter, it may be necessary to dissolve the member ligands 202 ofthe daughter libraries 200 in a solvent. The daughtering process isoptional because one may go directly from ligand synthesis to catalystformation; however, this has the disadvantage of using the entire ligandlibrary, meaning that the member ligands in the ligand library must bere-synthesized for experimentation beyond the first reaction orscreening experiment.

[0057] Once the daughter libraries are formed (or using the ligandlibrary), and continuing with FIG. 2, one or more metal precursors 204are added to at least a portion of the members 202 of the daughterlibraries 200 to create one or more libraries of target metal-ligandcomplexes, e.g., catalyst libraries 220. Combining may take place at oneor more daughtering stations or one or more combining stations. Each ofthe components or members or libraries to be combined is provided at thedaughtering or combining station and known robotic techniques may beused to transfer such components to the daughtering or combiningstation. Another option shown in FIG. 2 is to create daughter catalystlibraries 222 from the catalyst library 220 by taking one or morealiquot from the catalyst library. This may be done at a daughteringstation after at least the metal precursors and ligands have beencombined, with or without ligand modifiers or activators. This catalystdaughtering option may also be used when different activating optionsare being researched for the same ligand metal precursor combinations.Additionally, this option may be desirable when the same catalystlibrary will be tested for different reactions of interest or when thesame catalyst library will undergo the same reaction of interest atdifferent reaction conditions, such as with an optimization research anddevelopment program.

[0058] Once the catalyst libraries 220 or daughter catalyst libraries222 are prepared, the members 221,223 are subjected to a reaction ofinterest at either a reactor station or a screening station. Reactionsof interest may be performed in parallel or in a serial fashion.Different reactions of interest may be performed on daughter catalystlibraries or catalyst libraries. Referring again to FIG. 2, the catalystlibrary 220 may follow path X and be daughtered as discussed above intodaughter catalyst libraries 222. Path X shows a research path includingeither (1) reaction with screening or (2) reaction and subsequentscreening. Each catalyst library 220,222 is tested in a reaction ofinterest at a reaction station 80 to create one or more productlibraries 224. In parallel or serial fashion, the reactants are added tothe reactor with the catalyst members and the reaction is performedunder predetermined conditions. If a reactor is chosen with sensingcapabilities, then screening may take place during the reaction. Afterthe reaction, the results may be tested in post reaction screening 90for a property or a compound or a material. For example, if a smallmolecule transformation, such as aryl amination, is the reaction ofinterest then staining may be used to determine if the transformationhas occurred by choosing a stain appropriate for the product orreactant.

[0059] Path Y in FIG. 2 shows a research path having multiple reactionsand screens. The catalyst library 220 is daughtered into daughtercatalyst libraries 222 with the daughter libraries each being screenedin a primary screen 110. A primary screen is one that runs the reactionof interest, and provides sufficient data to determine at least whethera catalyst member was active in the reaction of interest or whether aproduct of interest was formed in the reaction. A primary screen may beone where the catalysts or products are not separated from each other,but subjected together to the reaction of interest in a parallel opticalscreen. For example, if the reaction of interest is the polymerizationof ethylene, the primary screen may be a chamber that allows ethylene tocontact all catalyst library members simultaneously. The activecatalysts may be identified from the inactive or less active catalyst byencoding the catalyst members of the catalyst library, as disclosed incopending U.S. patent application Ser. No. 09/033,207, filed Mar. 2,1998, which is incorporated herein by reference. The primary screen maybe an infrared screen that identifies active catalysts by heat ofreaction, such as disclosed in copending U.S. patent application Ser.No. 08/946,135, filed Oct. 7, 1997, which is incorporated herein byreference (published as WO 98/15815, which is also incorporated hereinby reference). The primary screen may be another optical technique todetermine if a product has been made; for example, if the reaction ofinterest is an emulsion polymerization, the optical screen may determineif an emulsion was created. Useful optical techniques are disclosed incopending U.S. patent application Ser. No. 08/947,085, and filed Oct. 8,1997, which is incorporated herein by reference (published as WO98/15805, which is also incorporated herein by reference). Anotherpossible primary screen is a parallel thin layer chromatography system,as disclosed in 09/062,128, filed Apr. 17, 1998 and incorporated hereinby reference. Other primary screens may be known or developed by thoseof skill in the art for specific reactions of interest.

[0060] Any screen may be a primary screen, however, the object of havinga primary screen is to eliminate some of the members 221, 223 of thecatalyst libraries or daughter catalyst libraries from further, moredetailed testing. Since an enormous number of ligands and metalprecursors are typically being combined in different routes, it may bethat one route is not applicable for a particular metal precursor/ligandcombination. A primary screen would eliminate such an inapplicable routeat a lower cost than a screen that provides more detailed information.As such primary screens are designed to quickly, effectively and/orefficiently reduce the number of catalyst members that are screened fordetailed information (such as conversion and selectivity or polymerparticle size).

[0061] Path Y also shows that after the primary screen 110, members ofcatalyst or product libraries 220,222, 224 that pass the primary screenare sent to a secondary screen 112. The secondary screen runs the samereaction of interest under conditions that supply more data than theprimary screen. Any of the screens discussed above may be a primary orsecondary screen. Another feature of FIG. 2 is a feedback loop 95 thatprovides information for the synthesis of new parent libraries or newdaughtering. The information comes from a post reaction screen 90, areaction that includes a screen 80, a primary screen 110 or a secondaryscreen 112. For example, the information sent in the feedback loop 95may be catalyst activity, compound existence or disappearance, polymerproperties or any other information that comes from the screens that areperformed. This feedback loop may be such as disclosed in U.S. Pat. Nos.5,563,564, herein incorporated by reference.

[0062] It will be readily apparent to those of skill in the art that theforegoing reaction and/or screening methods are intended to illustrate,and not restrict the ways in which the catalyst or product libraries canbe screened for useful properties for a reaction of interest. Otherscreening techniques and apparatuses known to those having skill in theart may similarly be employed.

[0063] An apparatus or system 500 for researching for novel ligands,catalysts or products is illustrated in FIG. 5. System 500 includes aparent library 502, a combining station 503, a daughtering station 504(to create one or more daughter libraries 506), optionally a filteringstation 508, a reaction station 510, a screening station 511 and anautomated robotic system, represented by arrows 512 to move librariesfrom one station to another. As used herein a “station” is a location inthe apparatus that performs one or more functions. The functions may becombining the starting components, combining ligands with metal atoms,ions or precursors, creating a product library via a reaction, screeningor any of the other functions discussed above. Thus, the station maycomprise a liquid handling robot with pumps and computers (as known inthe art) to dispense, dissolve, mix and/or move liquids from onecontainer to another. The station may include any of the reactorsdiscussed above, and may be in an inert atmosphere glove box. A locationin the apparatus may perform multiple functions, but for purposes ofdiscussing the methodology in block diagram form, each location orstation herein will be referred to as a separate station.

[0064] Basically, starting components or parent ligand libraries ormetal precursors, etc. are inputted into the apparatus (or retrievedfrom storage) and sent to a combining station 503. After combination,the product library is formed via reaction at the reaction station 510.If screening does not occur during the reaction, the product library issent to the screening station 511 for screening as discussed above. Adaughtering station 504 can be inserted into the process to createdaughter libraries 506. As discussed above, when ligands are beingcombined with metal precursors, this takes place at the combiningstation. Finally, a filtering station 508 may be used when solid phaseagents are used in the process.

[0065]FIG. 5 illustrates a block diagram flow for a methodology usefulin this invention. Starting components or parent libraries may bemaintained in storage and retrieved from storage and moved via thehandling system 512 to the combining station 503. Optional in thisprocess is the daughtering of the parent library at the daughteringstation 504. Multiple paths are shown from the daughtering station 504to the combining station 503 to show the possibility that multipledaughter libraries are transferred to the combining station 503. Thecombining station combines the starting components together in apredefined manner, using the components, ratios, etc. as discussedabove. Typically, exiting the combining station 503 is either a catalystlibrary or a combination of components for turning into a productlibrary. One option is for the results of the combination to go to afiltering station 508. Since filtering removes unwanted materials fromthe library (typically from the catalyst library), it may be desirableto daughter the library after filtering, which is accomplished at adaughtering station 504 between the filtering station 508 and thereaction station 510. The catalyst library or combination of startingcomponents proceeds to a reaction station 510, where the product libraryis formed. In other words, the reaction of interest is run at thereaction station 510. Process diversity is accomplished at the reactionstation 510 using the reaction options discussed above. From thereaction station 510, the product library proceeds to the screeningstation 511, where a predetermined screen is run to determine if thereaction of interest was successful and/or the qualitative orquantitative degree of success of the reaction of interest. Thescreening station may include a single screen or multiple screens (suchas a primary and secondary screen) and may entail using multiplelocations for the multiple screens. A feed-back loop 95 is provided thattakes screening information from either the reaction station 510 (when areaction that includes a screen is used) or the screening station 511.This screening information is used at the combining station 503 for newcombinations of starting components or creating new catalyst libraries,etc. The feed-back loop 95 may also feed screening information to thestarting components or parent libraries or the storage location for newproduct libraries to be created for making a product of interest.

[0066] The system 500 includes a computer or processor based system 514that controls, monitors and/or coordinates the process steps as well asinteraction between the various stations 503, 504, 508, 510 and 511. The“control” system also coordinates the movement of plates (parent ordaughter) moving in the robotic system 512. The “control” system 514also includes computers, processors and/or software that a user (e.g.,chemist) may use to interact with the system 500. Ideally, the controlsystem 514 contains sufficient hardware and software so that it is“user-friendly”, for example so that the amount of input by the user islimited to the essential design and process elements. The control system514 can comprise a central computer or processor to command, control andmonitor each subsystem or station or piece of the system 500.Alternatively, the control system 514 can comprise an integratedarchitecture with one or more of the subsystems, stations or pieces is asmart system of its own right. Thus, a user of the “control” system 514may design a set of experiments to create a product library, specify thescreen of that product library and command the system to perform all thechemistry and screening automatically from chemicals in storage.

[0067] For example, the “control” system 514 may command transportationof a library plate from storage to a combining station givinginstructions to the combining station that specify the types and volumesof chemicals to dispense. Another similar example is where similarinstructions are used with a daughtering station. The “control” system514 may also control the robotics 512 to move chemicals to the variousstations 503, 504, 508, 510 and 511. As a further example, the “control”system 514 may monitor and control the time that a plate remains at astation or the time that a reaction of interest is allowed to run, suchas by instructing a robot to add a catalyst kill to reactor vessels atvarious times. Still further, the “control” system may monitor andcontrol a screen, such as by moving a product library to the screeningstation and instructing an auto-sampling robot to sample the productlibrary with particular solvents for injection and into a molecularweight screen. Additionally, the “control” system 514 may collect,manipulate and/or store screening data. For example, the “control”system 514 may take data from a screen, reduce that data and then sendthe data for storage to a database. The “control” system 514 can alsomonitor the system 500 for safety, problems or other process issues. The“control” system may also include the feed-back loop 95, discussedelsewhere.

[0068] For example, robotic system 512 preferably includes an automatedconveyer, robotic arm or other suitable device that is connected to the“control” system 514 that is programmed to deliver the library plate 502or daughter plates 506 to respective stations 503, 504, 508, 510, 511.The processor is programmed with the operating parameter using asoftware interface. Typical operating parameters include the coordinatesof each of stations 503, 504, 508, 510, 511 in the system 500 as well asboth the library storage plate and daughter plates positioning locationsat each station. Other data, such as the initial compositions of eachligand modifier, metal precursor, activator and the initial compositionsof the ligands may also be programmed into the system.

[0069] In some embodiments, a library is stored in a storage plate 502,as more clearly seen in FIG. 6B. The library storage plate 502 includesa number of wells 604 formed therein that receive vials 606 containingthe library members, as shown in FIG. 6C. Each vial 606 may be providedwith a cap 608 having a septum 610 for protecting the members when beingstored. An optional lid 612 having latches 614 shown in FIG. 6B forconnecting to the storage plate 502 may also be provided for storagepurposes. FIG. 6A also shows that the library plate 502 may be stored ina rack 620 prior to transfer to the next station, such as a combiningstation 503 or daughtering station 504.

[0070] In a preferred embodiment, referring to FIG. 7, a combiningstation 503 or a daughtering station 504 includes a daughtering roboticarm 702 that carries a movable probe 704 and a turntable 706 for holdingmultiple daughter plates 506 while the daughtering step is beingperformed. Daughtering robotic arm 702 is movable. The robotic system512 manipulates the probe 704 using a 3-axis translation system. Theprobe 704 is movable between vials of ligand modifiers, metalprecursors, and activators arranged adjacent the synthesis station andplate.

[0071] Once the product libraries are created, the robotic handlingsystem 512 next transports plates to a screening station 511. As thissystem may be configured to perform multiple screening steps usingmultiple screening techniques, and there may be more than one screeningstation. It is preferred that plates containing the libraries each areeach receivable in a reactor blocks for the screening operation. Indeed,the plates may be the reactor block that is moved from one station tothe next. As disclosed in the copending applications, in one embodiment,the reaction block generally contains heating elements and temperaturesensing devices—thermocouples, thermistors, RTD's and other similardevices—that communication with a processor. The heating elements,temperature sensing devices, and the processor comprise a temperaturecontrol system that maintains the temperature of each of the catalystlibrary members at a pre-selected temperature during the reaction suchthat the catalysts may be analyzed as a function of temperature.

EXAMPLE

[0072] This an example of rapid light scattering screening of acombinatorial library that was prepared by controlled radicalpolymerization.

[0073] In a dry, nitrogen atmosphere glovebox stock solutions wereprepared using ligand L-1 having the structure shown below:

[0074] L-1 was synthesized from reductive coupling of4-(5-nonyl)pyridine using Pd/C catalyst at 200° C.

[0075] 1-chloro-1-phenylethane (hereinafter “I-1”) was synthesized bytreatment of styrene with HCl and purified by distillation. I-2 wassynthesized by reaction of commerially available divinylbenzene withHCl, followed by purification by distillation. I-2 had the followingstructure:

[0076] All other materials were commercially available and were purifiedusing conventional techniques.

[0077] Five stock solutions were prepared in a dry nitrogen atmosphereglovebox (I, II, I, IV, and V), as follows: Solution I comprised 19.8 mg(0.141 mmol) of 1-chloro-1-phenylethane (I-1) and 800 μL (6.98 mmol) ofstyrene. Solution II comprised 20 mg (0.2 mmol) CuCl, 174 mg of L-1(0.42 mmol), and 3.33 mL (29.1 mmol) of styrene. Solution III comprised14.2 mg of I-2 (0.07 mmol) and 800 μL (6.98 mmol) styrene. Solution IVcomprised 14.7 mg (0.105 mmol) of I-1, 10.4 mg (0.105 mmol) CuCl, 90 mg(0.022 mmol) of L-1, and 6 mL (52.4 mmol) of styrene. Solution Vcomprised 10.7 mg (0.0525 mmol) of I-2, 10.4 mg (0.105 mmol) CuCl, 90 mg(0.022 mmol) of L-1, and 6 mL (52.4 mmol) of styrene.

[0078] A 7-row by 12-column 84-vessel glass-lined aluminum reactor blockarray with approximately 800 μL volume per vessel was prepared in adrybox under dry nitrogen atmosphere and stock solutions I-V weremanually distributed to the vessels using a metering pipettor, such thatelements 1-5 received a gradient of Solution I (100 μL, 50 μL, 33.3 μL,25 μL, and 20 μL), 100 μL of Solution II, and a gradient of excessstyrene (0 μL, 50 μL, 66.7 μL, 75 μL, 80 μL). Elements 6-10 received agradient of Solution III (100 μL, 50 μL, 33.3 μL, 25 μL, and 20 μL), 100μL of Solution II, and a gradient of excess styrene (0 μL, 50 μL, 66.7μL, 75 μL, 80 μL). Elements 11-15 received a gradient of Solution I (100μL, 50 μL, 33.3 μL, 25 μL, and 20 μL), 100 μL of Solution II, a gradientof excess styrene (0 μL, 50 μL, 66.7 μL, 75 μL, 80 μL), and 200 μL ofdiphenylether. Elements 16-20 received a gradient of Solution III (100μL, 50 μL, 33.3 μL, 25 μL, and 20 μL), 100 μL of Solution II, a gradientof excess styrene (0 μL, 50 μL, 66.7 μL, 75 μL, 80 μL), and 200 μL ofdiphenylether. Elements 21-50 (a 5×6 array) received 150 μL of SolutionIV and a gradient of dilutions along each row by adding solvent (75 μL,150 μL, 225 μL, 300 μL, 375 μL, 450 μL) with a different solvent in eachrow (diethyl carbonate, benzene, o-dichlorobenzene, m-dimethoxybenzene,and diphenylether, respectively). Similarly, elements 51-80 (a 5×6array) received 150 μL of Solution V and a gradient of dilutions alongeach row by adding solvent (75 μL, 150 μL, 225 μL, 300 μL, 375 μL, 450μL) with a different solvent in each row (diethyl carbonate, benzene,o-dichlorobenzene, m-dimethoxybenzene, and diphenylether, respectively).In this fashion an array of 7×12 diverse polymerization reactions wereprepared, requiring a setup time of approximately 5 hrs. The reactorblock array was sealed using a Teflon membrane covering a silicon rubbersheet compressed with an aluminum plate bolted in place.

[0079] The reactor block array was then heated to 120° C. for 15 hrswith agitation provided by an orbital shaker. The reactor block arraywas allowed to cool, and to each vessel was added THF such that thetotal volume reached 0.8 mL, and the block was re-sealed and heated at105° C. with orbital shaking for approximately 1 hr, to allow formationof homogeneous fluid solutions. The reactor block was then allowed tocool.

[0080] Each element of the array was analyzed by rapid manner using thefollowing equipment and method:

[0081]FIG. 4 shows the general layout of the equipment including aneight port valve 1210 and a filter 1212. A light scattering detector1216 and a RI detector 1218 were used. Samples were injected into the8-port valve, having two 50-μl injection loops and the system wasmaintained at a temperature of 36° C. A short chromatographic column1214 (Polymer Laboratories, 1110-1520, sold as a GPC guard column) wasin-line between the filter 1212 and the light-scattering cell 1216.Samples were manipulated with a sampler 1200 automatically. The sampler1200 had a tip 1201 that obtained the polymer sample from the sampletray 1202. The sampler 1200 moved the tip 1201 into a loading port 1204that sent the sample through the transfer line 1206. The system wascontrolled by a single computer 1222 that controlled the sampler 1200,loading of the sample via the loading port 1204, as well as collectingdata from the light scattering detector 1216 and the RI detector 1218.

[0082] M_(w) for each sample was calculated using an algorithmincorporated in the analysis software (“Precision Analyze”, version0.99.031(Jun. 8, 1997), Precision Detectors) accompanying the PD2020. Inorder to determine Mw, points in the chromatogram representing thebaselines of the 15 and 90 degree signals and the RI signals were firstselected (“baseline regions”). Linear least-squares fits of these pointsdefined the three baselines. Then, an integration region encompassingthe main sample peak was chosen. The software then calculates M_(w)based on the SLS and RI data and baseline values in this integrationregion. The calculation was performed in the limit of the radius ofgyration, R_(g), being much less than the measurement wavelength, andthe polymer concentration in the dilute limit representing isolatedmolecules. This calculation also used the angular form-factor, P(θ),appropriate for a Gaussian-coil molecule, and fitted it to the SLSsignals to extract M_(w). For polymers with Mw less than about 10,000kD, this method determined values of M_(w) within less than 5% of valuescalculated assuming non-Gaussian-coil forms of P(θ).

[0083] R_(h) is calculated from the diffusion constant of the polymermolecules, which is obtained by fitting the photon-photon correlationfunction to an exponential. The PD2020 system was designed to allow formeasurements of R_(h) at each time-slice of the chromatogram forsufficiently low flow rates.

[0084] Using a programmable robotic sampler, 20 μL of each reactor weredrawn and dispensed along with 250 μL of THF into a polypropylenemicrotiter plate. 100 μL of this diluted sample was drawn and used toload a 50 μL sample loop on an HPLC injector, followed by rapid lightscattering evaluation. During the time of each analysis, the step ofdiluting the next sample was conducted, so that each sample injectionautomatically occurred at 40 sec. intervals. Table 1, below, shows theaverage M_(w)/1000 of the samples derived from the analysis. TABLE 1Col> Row 1 2 3 4 5 6 7 8 9 10 11 12 1 22.2 35.7 46.3 55.8 63.7 NR NR25.9 47.6 57.3 72 78.2 2 8.65 15 22.3 26.6 30.4 NR NR 11.2 19.8 33.140.1 42.9 3 28.9 20.2 16.6 12.6 12 11.9 44 34.3 29.8 20.9 17.6 16.4 438.9 29.6 26.1 24.1 24.2 22.9 56 51.7 45 38.7 30.9 27 5 47.8 34.8 23.618.6 15.4 14.1 59.9 48.3 33.7 25.2 22.6 18.3 6 40.6 28.6 15.3 12.9 1213.1 45.8 20.8 17.7 12.3 13.3 13.8 7 40.3 30.2 23.2 20.9 19.5 19.2 46.837.4 34.2 29.7 28.6 27.8

[0085] The expected trends of decreasing molecular weight withincreasing dilution, and decreasing molecular weight with decreasingmonomer to initiator ratio were observed. This demonstrates very rapidmolecular weight determinations in combinatorial discovery of optimalcatalytic processes.

[0086] It is to be understood that the above description is intended toillustrative and not restricted. Many embodiments will be apparent tothose of skill in the art upon reading the above description. The scopeof the invention should, therefore, be determined not with reference tothe above description, but should instead be determined with referenceto the appended claims, along with the full scope of equivalents towhich such claims are entitled. The disclosures of all articles andreferences, including patent applications and publications, areincorporated herein by reference for all purposes.

1. A system for the research or development of catalysts or polymers comprising: a storage area comprising two or more starting components; a combining station that receives said starting components and combines said starting components in different ratios; a reaction station that receives said different ratios of starting components and subjects said different ratios of starting components to a reaction of interest in parallel under reaction conditions thereby forming a product library of non-biological polymers; a daughtering station adapted to receive a sample of one or more of the non-biological polymer products from said product library to form a daughter library of non-biological polymers; and, a screening station equipped to receive the product or daughter library of non-biological polymers and screen said library for a property of interest.
 2. The system of claim 1, further comprising a filtering station between said combining station and reaction station.
 3. The system of claim 1, further comprising a transport system for transporting starting components or libraries from station to station.
 4. The system of claim 1, further comprising a control system for controlling or monitoring said system.
 5. The system of claim 4, wherein said control system collects data from said screening station and stores such data in a database.
 6. The system of claim 4, wherein said control system synchronizes the movement of plates in which said libraries are contained from one station to another.
 7. The system of claim 1, wherein said screening station is equipped to screen at least a portion the product or daughter library of non-biological polymers for molecular weight.
 8. The system of claim 1, wherein said screening station is equipped to screen at least a portion of the product or daughter library of non-biological polymers for particle size.
 9. The system of claim 1, wherein said screening station is equipped to screen at least a portion of the product or daughter library of non-biological polymers using Infrared thermography, Fourier Transform Infrared spectroscopy, thin layer chromatography, mass spectroscopy, gas chromatography or nuclear magnetic resonance. 